Mechanisms of neural tube closure

神经管闭合机制

基本信息

批准号：
10063062
负责人：
Sergei Sokol
金额：
$ 37.08万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063062
关键词：
Actomyosin Affect Anterior Apical Behavior Belief Biochemical Biological Biological Assay Biotinylation Brain Cell membrane Cell physiology Cells Complement Complex Congenital Abnormality Core Protein Defect Development Drosophila genus Embryo Epithelial Experimental Models Feedback Genes Genetic Models Genetic study Health Human Image Instruction Knowledge Ligands Light Mass Spectrum Analysis Mental disorders Modeling Molecular Morphogenesis Neural Tube Closure Neural Tube Defects Neural tube Neuraxis Neuroectoderm Neuroepithelial Pathway interactions Play Prevention Process Protein Analysis Proteins Regulation Role Signal Pathway Signal Transduction Signaling Protein Spinal Cord Surface System Testing Time Tissues Wnt proteins Xenopus base experimental study in vivo Model loss of function nervous system development nervous system disorder neural plate neuroepithelium neuromechanism novel planar cell polarity polarized cell protease-activated receptor 3 protein complex receptor recruit sensor vertebrate embryos

项目摘要

Neural tube closure is a morphogenetic process that involves complex behaviors of polarized neural plate cells. With more than 200 genes implicated in this process in genetic models, neural tube abnormalities are among the most common human birth defects. Nevertheless, mechanisms of neural tube closure remain poorly understood and the available vertebrate models are limited. Our preliminary experiments have identified a unique polarization of several proteins in the plane of the Xenopus neural plate and demonstrated that this polarity requires the functions of both planar cell polarity (PCP) and apical-basal polarity proteins. The proposed studies will carry out live imaging of the neural plate using a novel fluorescent sensor. New molecules that physically associate with the PCP complex will be identified using a novel proximity- and complementation- based biotinylation approach combined with mass spectrometry. The involvement of the apical-basal polarity proteins in PCP signaling during neural tube closure will also be evaluated. Xenopus embryos are easily accessible at any developmental stage and are uniquely suited for these studies, allowing rapid analysis of protein localization and function through a combination of biochemical, embryological and cell biological approaches. These experiments will shed light on basic signaling mechanisms that underlie normal development of the central nervous system. The proposed studies are highly relevant to human health, because misregulation of these signaling pathways leads to brain and neural tube defects and a variety of neurological disorders. .

神经管闭合是一个形态发生过程，涉及复杂的行为偏振神经板细胞。在此过程中实施了200多个基因遗传模型，神经管异常是最常见的人类诞生缺陷。然而，神经管闭合的机制仍然很了解，并且可用的脊椎动物模型有限。我们的初步实验已经确定了在异爪蟾神经板的平面和证明这种极性需要两个平面细胞极性（PCP）的功能和顶端极性蛋白。拟议的研究将进行实时成像使用新型荧光传感器的神经板。物理相关的新分子使用PCP复合物将使用新颖的接近和完成 - 基于质谱法结合了基于生物素化方法。参与神经管闭合期间PCP信号传导中的顶碱极性蛋白也将是评估。在任何发育阶段都可以轻松进入Xenopus胚胎，并且独特适合这些研究，可以快速分析蛋白质定位和通过生化，胚胎学和细胞生物学的结合功能方法。这些实验将阐明基本信号传导机制中枢神经系统正常发育的基础。拟议的研究是与人类健康高度相关，因为这些信号传导途径的不利导致大脑和神经管缺陷以及多种神经系统疾病。。